以斑马鱼为模式解析dnajb6b基因在扩张型心肌病中的功能和机制

扩张型心肌病是临床上最为常见的一种心肌病，可致心力衰竭和心源性猝死，是导致患者需要心脏移植的最主要病因。原发性扩张型心肌病具有很强的家族史和遗传易感性。本课题前期通过大量遗传筛选在斑马鱼模式中发现dnajb6b基因是一个新型的扩张型心肌病致病基因。在此基础之上，本项目拟进一步以斑马鱼为模式深入解析该基因在扩张型心肌病中的功能和分子作用机制。首先，本项目拟明确dnajb6b基因的心肌组织特异性表达在扩张型心肌病发生过程中的原发性功能；其次，本项目拟阐明dnajb6b 基因分别通过作用于肌质网钙泵（Serca2）和葡萄糖调节蛋白78（Grp78）来共同调控钙离子转运平衡和肌质网应激反应的分子机制；最后，本项目拟对从扩张型心肌病患者中鉴定到的人DNAJB6同源基因突变位点进行活体功能和机制验证，并测试靶向小分子药物在改善扩张型心肌病表型上的功效，从而有望为该病的防治提供新的基因和药物靶点。

Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy that can lead to heart failure and sudden cardiac death. It is also the most common diagnosis in patients who undergo cardiac transplantation. There is a strong genetic susceptibility for the primary DCM. Building on our preliminary data that identified dnajb6b as a new disease causative gene for DCM via zebrafish genetics, here, we propose to further decipher its function and underlying mechanisms. We will determine the primary function of dnajb6b in DCM in a cardiac tissue specific manner; We will further elucidate the critical roles of dnajb6b in regulating cardiac contraction and sarcoplasmic stress (SR stress) mediated by the sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (Serca2) and glucose regulated protein 78 (Grp78); Lastly, we propose to perform function validation analysis on DNAJB6 variants identified from patients with DCM, and to test the therapeutic efficacy of small molecules that specifically target to the Serca2 and SR stress pathways. Successful completion of this proposal is expected to identify novel gene and druggable targets for DCM.